The search for immunomodulator compounds and compositions has received much attention in recent years as the mechanisms by which the immune system produces protective or adverse physiological responses becomes more well known. The biological pathways involved in stimulation of the immune system, including stimulation of either or both innate immunity and adaptive immunity, are complex and allow numerous opportunities for the development of therapeutic treatments. For example, with the recent discovery of a family of receptor proteins known as Toll-like receptors (TLRs) believed to be involved in innate immunity as receptors for pathogen-associated molecular patterns (PAMPs), development of compounds suitable for therapeutic modulation of such receptors has gained in interest. A description of TLRs and their function in the immune response can be found in WO 2007/024612. Modulators of TLRs are potentially suitable as therapeutic agents for the treatment of, for example, conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease (GvHD), infection, cancer, and immunodeficiency.
Substituted benzazepine derivatives are a class of compounds that have been targeted as immune stimulants. In particular, 2-amino-4-carboxylate derivatives of benzazepines have been recognized for their ability to modulate TLRs and otherwise provide desirable immunotherapeutic responses.
EP 0 825 186 A1 describes preparation of 2-aminobenzazepine derivatives. The compounds are described as useful in the treatment of immunosuppression, for example by stimulating the production of Granulocytes and Granulocyte-Macrophage Colony Stimulation Factor. 2-aminobenzazepine derivatives are described having a variety of substituents including annulated rings, functional groups, and the like. The reference also describes the use of such compounds in the treatment of myelosuppression.
WO 2007/024612 describes preparation of 8-substituted benzazepines as TLR modulators. A procedure is disclosed for preparing (1E,4E)-ethyl-2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate. The procedure involves seven steps, including as the penultimate step the palladium-catalyzed cross-coupling reaction between (1E,4E)-ethyl-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate and 4-(pyrrolidine-1-carbonyl)phenylboronic acid. The reaction product from the cross-coupling reaction is purified by preparative LC. Following purification, an N—BOC deprotection step is carried out using TFA:DCM.
The use of metal-catalyzed cross-coupling reactions allows the preparation of 8-substituted benzazepine derivatives such as (1E,4E)-ethyl-2-amino-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate and the like. However, the palladium catalyst used in such reactions presents challenging purification obstacles. For example, where the benzazepine product is to be used as a pharmaceutically active agent, residual palladium waste left after the Suzuki reaction must be removed such that the concentration of palladium metal is within levels that are acceptable for pharmaceutical compositions. An ideal method of synthesizing benzazepine derivatives would, for example, provide product compounds in high yield with low levels of metal contamination. Preferably, such methods would avoid or minimize the use of purification by chromatographic methods. The present invention is directed at providing one or more of these desirable features.